Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
  • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
  • C07H17/06—Benzopyran radicals
  • C07H17/065—Benzo[b]pyrans
  • C07H17/075—Benzo[b]pyran-2-ones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• the present invention relates to novel 4-methyl-2-oxo-2H-1-benzopyran-7-yl 5-thio- ⁇ -D-xylopyranoside derivatives, to their use for the preparation of antithrombotic drugs and to the pharmaceutical compositions containing them.
• the invention further relates to a method for the preparation of these compounds.
• Patent EP 421 829 describes benzopyranone ⁇ -D-thioxylosides of formula (A): in which:
• These compounds are useful in the treatment and prevention of diseases associated with circulatory disorders, especially as venous antithrombotics.
• the compounds described in EP 421 829 are insufficiently soluble, especially in physiologically acceptable solvents, to allow them to be administered by injection. Thus they cannot be used in cases of emergency administration or on unconscious patients for whom injection is the only possible route of administration, or if it is preferable for the sake of convenience to administer one of these compounds in association with other drugs by perfusion.
• the present invention relates to novel 4-methyl-2-oxo-2H-1-benzopyran-7-yl 5-thio- ⁇ -D-xylopyranoside derivatives with an antithrombotic activity.
• These compounds have a good solubility in the conventional physiologically acceptable solvents, especially injectable solutions. They can therefore be administered both orally and by injection, especially intravenous injection.
• the invention therefore relates to the compounds of formula (I): in which:
• (C 1 -C 4 )alkyl group is understood as meaning a linear or branched, saturated hydrocarbon chain having from 1 to 4 carbon atoms.
• Examples of (C 1 -C 4 )alkyl groups include methyl, ethyl, propyl, butyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl groups.
• (C 1 -C 6 )alkyl group is understood as meaning a linear or branched, saturated hydrocarbon chain having from 1 to 6 carbon atoms. Examples of (C 1 -C 6 )alkyl groups include those listed above and also pentyl and hexyl groups.
• Salts are understood as meaning the addition salts obtained by reacting a compound of formula I, containing at least one basic functional group in its non-salified form, with a mineral or organic acid. Said addition salts will preferably be those which are pharmaceutically acceptable.
• Hydrochloric, hydrobromic, phosphoric and sulfuric acids are preferred among the mineral acids which are suitable for salifying a basic compound of formula I.
• Methanesulfonic and trifluoroacetic acids are preferred among the organic acids which are suitable for salifying a basic compound of formula I.
• the invention relates to a method for the preparation of the compounds of formula (I) which comprises the steps consisting in:
• the first step of the method of the invention is an esterification step, which can be carried out by the procedures well known to those skilled in the art.
• this esterification step is carried out with the aid of a coupling agent such as a carbodiimide, for example 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI), preferably in the presence of 1-hydroxybenzotriazole (HOBT).
• a coupling agent such as a carbodiimide, for example 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (EDCI), preferably in the presence of 1-hydroxybenzotriazole (HOBT).
• the esterification reaction is generally carried out in an anhydrous solvent, for example dimethylformamide (DMF), pyridine or dichloromethane, in the presence of an aprotic base such as triethylamine, 4-dimethylaminopyridine (DMAP) or mixtures thereof.
• an anhydrous solvent for example dimethylformamide (DMF), pyridine or dichloromethane
• an aprotic base such as triethylamine, 4-dimethylaminopyridine (DMAP) or mixtures thereof.
• the reaction is preferably carried out under a dry inert atmosphere, for example under a nitrogen or argon atmosphere, and in the presence of a moisture trap such as a molecular sieve.
• the reaction is advantageously carried out between room temperature and the reflux temperature of the solvent.
• the second step of the method of the invention is a salification step, which is carried out by methods well known to those skilled in the art, the compounds of formula (I) being reacted with mineral or organic acids, especially those which are pharmaceutically acceptable, for example hydrochloric acid, methanesulfonic acid or trifluoroacetic acid.
• the acids (III) and acid halides (IIIa) are commercially available compounds or are prepared by conventional methods.
• the compounds of formula (II) can also be obtained from the stannylene-type derivative of formula (IV): in which Bu denotes butyl, following the procedure described e.g. in J. Org. Chem. 1991,56,7015.
• ester-type functional groups of the compound (II) can be obtained selectively by reacting one or two equivalents of appropriate acylating agents of formula (IIIa) with the compound of formula (IV).
• radicals R 1 , R 2 and/or R 3 contain free amine groups, they are preferably protected with protecting groups so that the desired compounds of formula (I) can be obtained.
• the protection and deprotection reactions are carried out by the techniques well known to those skilled in the art.
• the tert-butoxycarbonyl group which is cleavable in an acid medium, will advantageously be used as the protecting group for the amine group.
• compounds (I′) the compounds of formula (II) protected in this way will be called compounds (I′). They are obtained by reacting the compounds of formula (II) with an acid or an acid halide of formula (III) or (IIIa) in which the groups R 1 , R 2 and R 3 are protected.
• the compounds according to the invention were the subject of pharmacological studies.
• the antithrombotic activity of the compounds according to the invention was studied in vivo in the rat by means of a test which reproduces venous thrombosis.
• the oral activity was studied according to the protocol described in Thromb. Haemost. 1992, 67(1), 176-179.
• the intravenous or oral activity was studied according to the following operating protocol:
• the experiments are performed on non-fasted Wistar male rats weighing 250 to 280 g, divided into groups of 10 animals each.
• the test products are administered either orally (tubage) dissolved or suspended in isotonic solution, or by intravenous injection dissolved in isotonic solution.
• the concentration of the compounds is calculated so that the amount of solution absorbed is 2 ml/kg by oral administration and 1 ml/kg by intravenous injection.
• Thrombosis is induced at a time T (2, 4 or 8 hours) after the administration of the product, and the thrombus formed is removed and weighed. To induce this thrombosis, a venous stasis is created under hypercoagulation according to the technique described by WESSLER ( J. Applied Physiol.
• the hypercoagulating agent used being a solution of activated factor X (Xa) having a concentration of 7.5 nKat/kg, supplied by Biogenic.
• the activity of the test compounds was checked at different doses after they had been administered either orally (p.o.) or intravenously (iv.).
• the thrombosis was induced 4 hours or 8 hours after oral administration of the compound and 2 hours after intravenous administration of the compound.
• doses varying between 8 and 17 mg p.o. the percentage inhibition obtained after 4 hours, calculated relative to the weight of a thrombus obtained in the absence of active principle in the isotonic solution, varied between 40 and 99%.
• the percentage inhibition obtained after 2 hours varied between 40 and 95%.
• the present invention therefore relates to the compounds of formula (I) according to the invention, and their pharmaceutically acceptable salts, solvates and hydrates, for use as drugs.
• the compounds of formula (I), or one of their pharmaceutically acceptable salts, solvates or hydrates may be used for the preparation of an antithrombotic drug intended in particular for the treatment or prevention of disorders of the venous circulation and especially for correcting certain hematological parameters perceptible in the venous system.
• the present invention therefore further relates to pharmaceutical compositions containing a compound of formula (I) or one of its pharmaceutically acceptable salts, solvates or hydrates.
• These pharmaceutical compositions generally contain suitable excipients. Said excipients are chosen according to the desired pharmaceutical form and the desired mode of administration, particularly oral administration or administration by injection.
• compositions are prepared by the conventional methods well known to those skilled in the art.
• the compounds according to the invention can be formulated with physiologically acceptable excipients to give an injectable form for direct use, an injectable form to be prepared immediately before use, or a solid form for oral administration, for example a gelatin capsule or a tablet.
• an injectable form can preferably be prepared by the lyophilization of a sterilized filtered solution containing the compound according to the invention and a soluble excipient in a necessary and sufficient amount to give an isotonic solution after the addition of injectable water immediately before use.
• An oral form will preferably be presented in the form of a gelatin capsule containing the finely ground or, preferably, micronized compound of the invention mixed with excipients known to those skilled in the art, for example lactose, pregelatinized starch and magnesium stearate.
• each unit dose can contain 25 to 500 mg of at least one compound according to the invention.
• DMSO dimethyl sulfoxide
• the reaction mixture is then stirred for 18 hours.
• the precipitate is filtered off and rinsed with 30 ml of ethyl acetate.
• the filtrate is concentrated and the residual orange oil is taken up in 100 ml of water and 15 ml of triethylamine.
• the aqueous phase is extracted with ethyl acetate (100 ml+50 ml).
• the organic phases are combined and washed with 50 ml of water and then with 50 ml of saturated aqueous sodium chloride solution.
• the organic phase is then dried over magnesium sulfate, filtered and concentrated.
• EXAMPLE 1A The corresponding trihydrochloride (EXAMPLE 1A) is prepared by adding 7.5 ml of a 1 M solution of hydrogen chloride in diethyl ether to a solution of 0.7 g of the compound of EXAMPLE 1 in 3 ml of anhydrous methanol at 0° C. A yellowish paste then forms instantly. The mixture is subsequently diluted with 5 ml of anhydrous diethyl ether, stirred at 0° C. for 1 hour and then concentrated to give a yellowish solid.
• EXAMPLES 2 to 5A shown in TABLE 1 below are prepared by following the same procedure starting from the corresponding acid (III), in the presence or absence of HOBT.
• the compound of EXAMPLE 12 is prepared from the compound II.1 and N-(tert-butoxycarbonyl)-N-methylglycine by a procedure analogous to that of EXAMPLES 11 and 11A.

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• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• General Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Diabetes (AREA)
• Hematology (AREA)
• Biochemistry (AREA)
• Biotechnology (AREA)
• Genetics & Genomics (AREA)
• Molecular Biology (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Saccharide Compounds (AREA)

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Citations (1)

• 2001
  • 2001-05-11 FR FR0106236A patent/FR2824559B1/fr not_active Expired - Fee Related
• 2002
  • 2002-05-06 US US10/139,908 patent/US6927209B2/en not_active Expired - Fee Related
  • 2002-05-07 SK SK1376-2003A patent/SK13762003A3/sk unknown
  • 2002-05-07 MX MXPA03010259A patent/MXPA03010259A/es not_active Application Discontinuation
  • 2002-05-07 BR BR0209102-0A patent/BR0209102A/pt not_active IP Right Cessation
  • 2002-05-07 JP JP2002589497A patent/JP2004534036A/ja not_active Withdrawn
  • 2002-05-07 RU RU2003132704/04A patent/RU2003132704A/ru not_active Application Discontinuation
  • 2002-05-07 EP EP02738222A patent/EP1385858B1/fr not_active Expired - Lifetime
  • 2002-05-07 WO PCT/FR2002/001573 patent/WO2002092614A1/fr active IP Right Grant
  • 2002-05-07 EE EEP200300548A patent/EE200300548A/xx unknown
  • 2002-05-07 PL PL02369632A patent/PL369632A1/xx not_active Application Discontinuation
  • 2002-05-07 CA CA002446763A patent/CA2446763A1/fr not_active Abandoned
  • 2002-05-07 IL IL15858702A patent/IL158587A0/xx unknown
  • 2002-05-07 CZ CZ20033021A patent/CZ20033021A3/cs unknown
  • 2002-05-07 KR KR10-2003-7013501A patent/KR20030094351A/ko not_active Application Discontinuation
  • 2002-05-07 HU HU0304065A patent/HUP0304065A2/hu unknown
  • 2002-05-07 DE DE60210595T patent/DE60210595D1/de not_active Expired - Fee Related
  • 2002-05-07 AT AT02738222T patent/ATE323097T1/de not_active IP Right Cessation
  • 2002-05-07 CN CNA028097033A patent/CN1518557A/zh active Pending
  • 2002-05-08 AR ARP020101682A patent/AR035880A1/es unknown
• 2003
  • 2003-10-24 ZA ZA200308317A patent/ZA200308317B/en unknown
  • 2003-11-10 NO NO20034985A patent/NO20034985D0/no not_active Application Discontinuation
  • 2003-11-11 BG BG108347A patent/BG108347A/bg unknown

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